Although caloric restriction is known to prolong life and obesity is known to shorten life in many species including many mammalian species, many questions remain unanswered at both the level of basic biology and the public health/clinical level. For practical, theoretical, and ethical reasons it is impossible to randomly assign humans to different levels of body weight, fatness, or fat distribution or different degrees of weight stability and to then follow them for the entire lifespan. Yet, questions about the effects of such body weight and composition variables remain. Model organism studies are a key aspect of the totality of evidence that can be brought to bear on such questions by offering rigorously controlled full-lifespan experiments that can complement other types of studies that can be done in humans. The research proposed addresses questions such as: Among obese organisms, must weight loss be sustained to be beneficial with respect to lifespan? Are repeated bouts of weight loss and regain (i.e., 'weight cycling') beneficial, harmful, or neutral? To what extent do the beneficial effects of weight loss among obese organisms result from reductions in total fat, visceral fat, metabolic rate, or adipocyte size. These questions will be addressed in a randomized lifespan experiment in dietary obese mice using state-of-the-art body composition, metabolic assessment, and statistical analysis methods, supplemented with small targeted mechanistic sub-studies. These questions have implications for basic science in terms of opening and prioritizing pathways to explore as mediators of the salubrious effects of weight loss and caloric restriction and implications for strengthening, weakening, or refining clinical recommendations concerning the types of behavioral and anatomic alterations likely to enhance longevity among obese humans. PUBLIC HEALTH RELEVANCE: Over 50 million Americans are obese and are therefore predicted to live less long than they would otherwise live. Whether reductions in overall obesity or selected aspects of fatness among obese persons will prolong life remains the subject of active debate and controversy. The proposed research will help provide information to inform that dialogue.